RHBDL4-triggered downregulation of COPII adaptor protein TMED7 suppresses TLR4-mediated inflammatory signaling

• Published in: Nature communications 2024-03, Vol.15 (1), p.1528-1528, Article 1528
• Main Authors: Knopf, Julia D., Steigleder, Susanne S., Korn, Friederike, Kühnle, Nathalie, Badenes, Marina, Tauber, Marina, Theobald, Sebastian J., Rybniker, Jan, Adrain, Colin, Lemberg, Marius K.
• Format: Article
• Language: English
• Subjects: 13/31; 14; 631/250/256; 631/80/313/1463; 631/80/474/2287; 82/1; 82/29; 82/58; Adaptor proteins; Adaptor Proteins, Signal Transducing - metabolism; Animals; Cell activation; Cell Membrane - metabolism; Cell surface; Cell walls; Child; Down-Regulation; Feedback loops; Humanities and Social Sciences; Humans; Immune system; Inflammatory diseases; Innate immunity; Kinases; Lipopolysaccharides; Lipopolysaccharides - metabolism; Macrophages; Medical research; Membrane trafficking; Mice; Mucocutaneous lymph node syndrome; multidisciplinary; Negative feedback; Pattern recognition; Pattern recognition receptors; Protease; Proteins; Science; Science (multidisciplinary); Septic shock; Signal Transduction; TLR4 protein; Toll-Like Receptor 4 - metabolism; Toll-like receptors; Transcription activation; Veterinary medicine
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-45615-2

The toll-like receptor 4 (TLR4) is a central regulator of innate immunity that primarily recognizes bacterial lipopolysaccharide cell wall constituents to trigger cytokine secretion. We identify the intramembrane protease RHBDL4 as a negative regulator of TLR4 signaling. We show that RHBDL4 triggers degradation of TLR4’s trafficking factor TMED7. This counteracts TLR4 transport to the cell surface. Notably, TLR4 activation mediates transcriptional upregulation of RHBDL4 thereby inducing a negative feedback loop to reduce TLR4 trafficking to the plasma membrane. This secretory cargo tuning mechanism prevents the over-activation of TLR4-dependent signaling in an in vitro Mycobacterium tuberculosis macrophage infection model and consequently alleviates septic shock in a mouse model. A hypomorphic RHBDL4 mutation linked to Kawasaki syndrome, an ill-defined inflammatory disorder in children, further supports the pathophysiological relevance of our findings. In this work, we identify an RHBDL4-mediated axis that acts as a rheostat to prevent over-activation of the TLR4 pathway. Toll-like receptor 4 (TLR4) is a key pattern recognition receptor that primarily responds to ligation of bacterial lipopolysaccharide. Here the authors suggest the intramembrane protease RHBDL4 as a regulator of TLR4 signaling.